Captopril analogues

The structural relationship of pivopril to the commercially important analogues captopril (51) and enalaprilat (52) is readily apparent. 

Fig. 7.19 Design of rapidly cleared ester analogues of sulfentanil propranolol and captopril. The compounds remifentanil, esmolol and FPL 66564 are all cleared to inactive metabolites.

An analogue of the drug captopril (1) was prepared by Vasella et al.234) by a similar approach. In this case the diastereoselectivity was very low. 

Captopril (14) is a competitive inhibitor of ACE, with K, = 1.7 x 10-9 M. Its inhibitory activity does not increase with time and is reversible on dilution. These properties and the analogue studies referenced above support its designation as an active site inhibitor not functioning by... 

There appear to be significant differences between the pioneer drug, captopril, and the enalapril analogues. Differences in these characteristics influence mainly the onset and duration of action. Captopril has a short onset time (1 h) and a relatively short duration of action, and therefore is administered three times daily. Captopril has potential drug-food interactions, and is the only agent that should be spaced from meals. Therefore, captopril is no longer used as a first-choice ACE-inhibitor in clinical practice, except for hypertensive emergencies, acute myocardial ischemia, and acute CHF. 

The pioneer drug, captopril, had a relatively short duration of action. Nonetheless, with sublingual administration it is used to elicit beneficial hemodynamic and clinical effects in hypertensive crises, acute myocardial ischemia, and acute CHF. Several long-acting analogue drugs are used nowadays as a first-choice therapy in cardiovascular diseases, and their minor differences have been summarized in this chapter. 

A new orally active CE inhibitor, SA-291 (A), is the most potent of a series of thiazolidine analogues of captoprll. l The SAR appears similar to that found for captopril and SA-291 shows the same spectrum of activity as captopril in animals. 

Following the introduction of captopril (48), an orally active angiotensin-converting enzyme inhibitor (ACE), many proline-containing analogues have been prepared for treatment of hypertension and congestive heart failure). One of the most active derivatives is... 

A good example is the development of the angiotensin converting enzyme (ACE) inhibitors successfully used in the treatment of hypertension. A careful study of the natural substrate and peptide inhibitors of this enzyme led first to captopril followed by enalapril (see above). The former is considered an analogue of a proline dipeptide and the latter a proline tripeptide analogue. 

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